Introduction
The retina is a layer of neurosensory tissue in the eye that converts light into neural signals that the brain interprets as images. The macula is the part of the retina with the highest concentration of cones, which are essential for central vision. Wet age-related macular degeneration (ARMD), also known as exudative or neovascular ARMD, primarily affects the macula and is the most common cause of central visual impairment and blindness among elderly individuals in developed countries.
Vascular endothelial growth factor (VEGF) drives the development of choroidal neovascularization (CNV), where new vessels grow under or through the retinal pigment epithelium (RPE) via breaks in the Bruch membrane. Regular administration of intravitreal anti-VEGF medications may prevent blindness in most of these patients. Without such treatment, patients with wet ARMD experience severe, irreversible vision loss.
Etiology
Wet ARMD is a multifactorial disease, and numerous risk factors have been identified in its progression. These risk factors include older age, elevated total serum cholesterol, micronutrient deficiency, smoking, family history, hypertension, cardiovascular disease, and visible light exposure. There appears to be a genetic predisposition to ARMD, with at least 34 genetic loci and 52 gene variants linked to the disease.
Many studies have also shown the key role inflammation plays in the pathogenesis of wet ARMD. Most notably, polymorphisms of complement factor H, which normally act to inhibit the alternative complement pathway, are among the best-known mutations in ARMD, suggesting the important role of complement activation in its development.
Epidemiology
In 2015, ARMD was the third most common cause of moderate to severe visual impairment globally. The global prevalence of ARMD among those aged 45 to 85 years old was 8.7%, with a prevalence of 0.4% for advanced ARMD. Early ARMD is more common among those of European ancestry than in Asians, and ARMD of any stage is less common in individuals of African ancestry. The global prevalence of any stage of ARMD is predicted to increase from 196 million people in 2020 to 288 million by 2040.
Approximately 10% of patients with ARMD develop neovascular disease. In the absence of anti-VEGF therapy, between 79% to 90% of those eyes will eventually become legally blind due to complications from neovascularization.
Pathophysiology
Wet ARMD is differentiated from early or dry ARMD by the presence of choroidal neovascularization (CNV), where new blood vessels from the choroid penetrate through the Bruch membrane and proliferate either between Bruch’s membrane and the RPE or in the subretinal space. Various factors contribute to the development of CNV and vision loss in patients with wet ARMD. These factors include:
VEGF accumulation, particularly the VEGF (165) isoform
Growth of new blood vessels with the proliferation of fibrous tissue
Leakage of proteins and lipids from the new vessels
Hemorrhage from the fragile new vessels
Fibrovascular scar formation, with the death of the neurosensory retina and vision loss
History and Physical
Patients with wet ARMD typically report visual distortion or blurring of central vision, especially their near vision. Other patients report metamorphopsia, micropsia, or scotoma, although some may report no symptoms or only vague vision complaints.
On examination, patients frequently have decreased best-corrected visual acuity (BCVA), and Amsler grid evaluation may reveal areas of central or paracentral scotoma or visual distortion. Ophthalmic examination of the anterior segment of the eye is usually normal. ARMD-related CNV has several different appearances on the dilated funduscopic exam. These include:
A gray-green membrane deep into the retina is usually associated with an overlying neurosensory retinal detachment.
There may be the presence of blood, lipid, or subretinal fluid.
RPE detachments appear clinically as dome-shaped, sharply demarcated elevations of the RPE; these may also be serous, fibrovascular, drusenoid, or hemorrhagic.
There may be massive subretinal hemorrhage with central vision loss or, less commonly, breakthrough vitreous hemorrhage with peripheral vision loss.
RPE tears.
Disciform scars may be present, which may appear as white or yellow subretinal membranes with or without RPE hyperplasia.
Evaluation
Optical Coherence Tomography (OCT)
OCT is a noninvasive imaging modality that can capture detailed images of the retina and surrounding structures. It uses low-coherence light beams directed toward the target tissue, and the reflected light is combined with a reference beam and measured to create an interference pattern. This is used to reconstruct an axial A-scan. Multiple A-scans can be used to reconstruct a cross-sectional B-scan. From there, raster scans and even 3-dimensional images can be produced. Wet AMD is characterized by the following findings on OCT:
Subretinal and intraretinal fluid
Serous retinal pigment epithelial detachment (PED) is seen as a homogenously hyporeflective space between the RPE and Bruch’s membrane
Fibrovascular PED (FVPED), which shows layers of moderate hyperreflectivity between the RPE and Bruch’s membrane separated by hyporeflective clefts
Hemorrhagic PED, which appears as a large, dome-shaped, hyperreflective lesion between the RPE and Bruch’s membrane with attenuation of deeper structures
RPE tears manifest as areas of discontinuity in a large PED; the RPE edge may be seen curled under the PED
Disciform scarring, with subretinal hyperreflective material and loss of the ellipsoid zone
OCT angiography (OCT-A) is a newer technology that creates images of the retinal circulation by obtaining sequential B scans from a single area, and decorrelation signals are generated to show only areas with movement (i.e., flow-through vessels). It may be useful in the earlier diagnosis of CNV, even before such lesions can be detected by conventional OCT or fluorescein angiography imaging.
Fluorescein Angiography (FA)
FA should be considered early in diagnosing wet ARMD to prevent an error in diagnosis. OCT, the most frequent imaging modality used to make retreatment decisions in wet ARMD, is 85% sensitive yet only 48% specific for diagnosing active wet ARMD. Thus, treatment decisions made solely on OCT findings may result in overtreatment. Common FA patterns in wet ARMD include:
Classic CNV is characterized by well-demarcated areas of hyperfluorescence present in early phases of imaging with mid and late leakage.
Occult CNV is characterized by either 1) an FVPED that demonstrates stippled hyperfluorescent dots with pooling, with or without leakage, or 2) late leakage of an undetermined source (LLUS), often presenting as speckled hyperfluorescence with subretinal pooling of dye
Retinal angiomatous proliferation (RAP) is characterized by anastomosis between retinal and choroidal vessels and shows early hyperfluorescence, intraretinal hemorrhage, and vessels diving at right angles from the retina to the area of CNV
Serous PED can present with early, bright hyperfluorescence that is uniform in appearance and demonstrates little to no leakage
Hemorrhagic PED is characterized by the blocking of underlying choroidal fluorescence
Drusenoid PED, with only faint fluorescence and lack of late staining or leakage
Speckled hyperfluorescence
Loculated fluid with pooling of fluorescein dye anterior to the area of CNV
RPE tears manifest as early hyperfluorescence with late staining of the choroid and sclera without leakage
Disciform scars, which may show leakage and staining or blocking if there is RPE hyperplasia
Indocyanine Green Angiography (ICGA)
Indocyanine green is a dye that is useful for imaging the choroidal circulation since it is highly protein-bound and less likely to leak from the fenestrations in choroidal vessels. ICGA is especially helpful in delineating occult CNV, which may manifest as either 1) a hot spot or area of early- to mid-phase hyperfluorescence, 2) a plaque or area of late hyperfluorescence, or 3) an area of poorly-defined fluorescence. ICGA may be used to identify feeder vessels in CNV that may be treated with laser photocoagulation. It may also better compare subtypes of CNV, allowing for earlier diagnosis and determination of patient prognosis.
Treatment / Management
Intravitreal Anti-VEGF Therapy
The first FDA-approved intravitreal anti-VEGF agent for wet ARMD was Pegaptanib sodium, a VEGF(165)-specific antagonist. However, this has since been replaced by bevacizumab, ranibizumab, and aflibercept due to improved results in various trials. Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF. Bevacizumab, approved by the FDA for metastatic colorectal carcinoma, is used off-label as a treatment for ARMD. It is non-inferior to ranibizumab for this purpose. Aflibercept acts as a VEGF receptor decoy, effectively trapping all VEGF isoforms. Every two months, aflibercept dosing is as effective as monthly ranibizumab dosing. Additionally, several ranibizumab biosimilar agents were recently approved for use in the United States, including ranibizumab-nuna and ranibizumab-eqrn.
Brolucizumab is a low molecular weight VEGF antagonist that allows for a higher molar concentration of medication with each injection. It was recently approved by the FDA and found to be non-inferior to aflibercept with every twelve-week dosing Despite early success with brolucizumab, there exist concerns regarding reports of severe intraocular inflammation and vasculitis following administration.
Faricimab is an antibody with affinity for both VEGF and angiopoietin-2 (Ang-2), an additional factor that may drive inflammation and contribute to CNV development. Early reports of faricimab are promising, with extended dosing intervals of 16 weeks shown to be non-inferior to ranibizumab every four weeks. Faricimab was approved for use in the United States in early 2022.
Although approved for monthly (ranibizumab), bimonthly (aflibercept), every three months (brolucizumab), or up to every 16-week (faricimab) injections, several different dosing regimens have been suggested in the literature, these include a pro re nata (PRN or as needed) schedule where a patient receives injections only when the disease appears active (such as in the presence of subretinal/intraretinal fluid on OCT, retinal hemorrhage, or leakage on FA) or a treat-and-extend protocol, where injection frequency is slowly extended as long as disease activity remains controlled.
Although monthly injections are more effective than PRN regimens, there is inconclusive evidence comparing PRN versus treat-and-extend. Endophthalmitis is likely more common with monthly injections, and patients receive more injections with monthly and treat-and-extend dosing than with PRN. However, patients require more frequent clinic visits with PRN dosing than with treat-and-extend.
Long-term data suggest that PRN dosing may result in slightly worse visual outcomes than monthly injections after a year. Although this difference may be clinically insignificant after a year, it may become significant after several years of treatment. Ultimately, the physician and patient should work together to choose the best treatment option for the patient.
Intravitreal anti-VEGF agents come with several risks. Common adverse effects include subconjunctival hemorrhage and discomfort during or after the procedure, usually from the iodine-based antiseptic used to clean the ocular surface. Floaters may be caused by bubbles in the syringe or the medication itself. Rarely serious adverse events occur, including vitreous hemorrhage or endophthalmitis. Several studies have also explored potential systemic adverse events related to intravitreal anti-VEGF administration, including the risk of myocardial infarction, stroke, non-ocular hemorrhage, or thromboembolic events. There is currently inadequate evidence to suggest an increase in systemic morbidity or mortality from the intravitreal administration of anti-VEGF agents. However, this theoretical risk is still important to discuss with patients, especially those deemed higher risk.
Other treatments are still under investigation. Abicipar pegol is a non-monoclonal antibody developed with designed ankyrin repeat proteins (DARPin) technology, with VEGF binding affinity similar to aflibercept. Like brolucizumab, its use may be limited due to higher reported rates of intraocular inflammation. It was not approved by the FDA.
Conbercept is a VEGF decoy protein, similar to aflibercept, that appears to have increased binding capacity to VEGF with an extended intraocular half-life, and FDA studies are currently underway. Additionally, several sustained-release delivery devices are in development to help decrease the burden of frequent intravitreal injections and help reduce the potential for undertreatment. The ranibizumab Port Delivery System (PDS), which was approved for use in the United States in 2021 and requires refill exchanges every 24 weeks, was shown to be non-inferior to monthly ranibizumab. However, the PDS had a higher risk of adverse events compared to ranibizumab monthly injections, including higher rates of endophthalmitis, retinal detachments, vitreous hemorrhages, conjunctival erosions, and conjunctival retractions.
Other Treatments
Before the widespread use of anti-VEGF therapy, several other treatment modalities were employed for wet ARMD. Laser photocoagulation is beneficial for fovea-sparing CNV lesions, although failure to adequately cover the entire lesion can lead to treatment failure and vision loss. Since laser photocoagulation destroys the overlying retinal tissue, this treatment should not be used for foveal-involving lesions, which are more likely to be visually devastating for patients.
Photodynamic therapy (PDT) is another treatment for CNV where the photosensitizing drug verteporfin is injected intravenously, and a low-intensity laser light treats the CNV tissue through a photochemical reaction that damages vascular endothelial cells, causing thrombosis. Despite the lower intensity laser used in PDT, most patients still lose some vision after treatment. Anti-VEGF therapy has largely supplanted both laser photocoagulation and PDT in the treatment of wet ARMD.
Submacular surgery for patients with wet ARMD has shown no benefit in patients with subfoveal CNV, and it comes with the risk of cataract progression and retinal detachment. Other surgical approaches for patients with CNV and vision loss include macular translocation surgery and mechanical displacement of subretinal hemorrhage with gas. There is still insufficient evidence to recommend macular translocation to patients unless a patient has severe, bilateral disease that does not respond to anti-VEGF therapy.
Pneumatic displacement of submacular hemorrhage, using intravitreal air or gas injection with face-down positioning, may improve a patient’s visual acuity in the short term, but the long-term benefit may not be achieved if the underlying CNV remains active. Even in these patients, anti-VEGF therapy may be sufficient without surgical intervention.
Radiation therapy has been considered for CNV in wet ARMD, but studies have not shown a clear benefit. Radiation therapy in combination with intravitreal ranibizumab is inferior to as-needed use of ranibizumab monotherapy. There is currently no evidence to support the use of radiation therapy in wet ARMD.
An exciting new avenue of treatment for wet ARMD is the use of gene therapy. RGX-314 is an AAV8 vector expressing an anti-VEGF-A Fab similar to ranibizumab, and subretinal delivery of the medication has been shown to be generally safe and well-tolerated. Phase 2 and 3 trials are currently underway to test the safety and efficacy of subretinal and suprachoroidal delivery of RGX-314.
Differential Diagnosis
The differential diagnosis for CNV from wet ARMD should include other causes of CNV. These include:
Breakthrough vitreous hemorrhage can also occur in wet ARMD, and diagnosis may be challenging if there is a poor view on dilated funduscopic examination. Diagnosis may be established by evaluating the patient’s fellow eye or obtaining a thorough history. Other potential causes of vitreous hemorrhage include:
Proliferative diabetic retinopathy
Retinal tear or retinal detachment
Hemorrhagic posterior vitreous detachment
Neovascularization from other causes, including vein occlusions, radiation retinopathy, or sickle cell retinopathy
Polypoidal choroidal vasculopathy (PCV) is a subtype of ARMD that is more common in Asian patients. It is characterized by orangish-red, bulb-like subretinal polyps associated with adjacent subretinal hemorrhage or exudates. ICGA is an essential tool in the diagnosis of PCV, and recurrent disease is more common among PCV patients than those with wet ARMD. Patients with PCV may benefit more from PDT than typical wet AMD patients.
Prognosis
Over 2-3 years without treatment, 50-60% of eyes with wet ARMD and subfoveal CNV will lose 6 or more lines of vision, compared to 20 to 30% of eyes with any submacular CNV. Classic CNV is associated with worse visual outcomes than occult or minimally classic CNV, and up to half of the patients with no classic lesions on initial presentation may develop classic CNV within a year after diagnosis.
Eyes with large subretinal hemorrhages that involve the fovea often have poor visual outcomes, although some eyes have surprisingly good visual recovery, suggesting that prompt treatment (such as with intravitreal anti-VEGF medications or surgery) is still beneficial. RPE tears involving the fovea also generally result in poor visual acuity and an elevated risk of vision loss from an RPE tear in the fellow eye.
Complications
Untreated, wet ARMD leads to irreversible loss of vision in a majority of patients. Even with treatment, vision loss can still occur. Patients with vision loss from ARMD often report a diminished quality of life. They report significantly more emotional distress, poorer health, and less independence in daily activities than people with other chronic illnesses.
Deterrence and Patient Education
All patients with macular drusen should be educated on the importance of regular Amsler grid use to check for metamorphopsias or scotomas that may indicate conversion from dry to wet ARMD. Any change in near or distance vision may also indicate developing CNV, and patients should be instructed to contact their ophthalmologist without delay. Patients may also benefit from lifestyle modifications, including eating a well-balanced diet with plenty of micronutrients, sunglasses to avoid excessive visible light exposure, and regular exercise. They should regularly see their primary care physician and control any underlying systemic disorders. Select patients should also be encouraged to regularly use Age-Related Eye Disease Study (AREDS) or AREDS2 vitamins, including vitamin C/E, beta-carotene, or lutein/zeaxanthin, cupric oxide, and zinc. These vitamins have been shown to prevent the progression to advanced ARMD in patients with an intermediate disease or advanced disease in one eye.
Patients who already have severe vision loss may benefit from visual rehabilitation and referral to a low-vision clinic, where they can learn about resources to help them function with their limited vision. Several low-vision tools can be offered, including handheld magnifiers, closed-circuit television viewers, or accessibility apps on common electronic devices, including both smartphones and tablets. In addition, they should be counseled on the availability of large-print periodicals, audiobooks, and other resources offered by their local library and available through the Library of Congress. They may also benefit from referral to social services to help them preserve their independence as much as possible.
Enhancing Healthcare Team Outcomes
Patients with ARMD are usually evaluated by an interprofessional healthcare team which may include a referral to a retina specialist. Primary care providers, optometrists, and general ophthalmologists play a key role in recognizing the signs and symptoms of worsening wet ARMD and referring patients to a retina specialist or other provider trained in the evaluation of wet ARMD and administration of intravitreal injections. Expeditious diagnosis and treatment are crucial to preventing irreversible vision loss. Pharmacists can provide the team and the patient with information on the drugs used, including potential interactions and adverse events, and verify proper dosing. Interprofessional teamwork will help yield the best possible patient outcomes in ARMD. [Level 5]
Although some believe that only retina specialists are qualified to administer intravitreal anti-VEGF agents, there is a shortage of such specialists, especially in rural areas. This, along with the growth of the aging population in the United States and other developed countries, has led to more comprehensive ophthalmologists learning how to evaluate and treat patients with wet ARMD. Despite this trend, comprehensive ophthalmologists should understand that care for patients with wet ARMD requires complex decision-making based on individual vitreoretinal pathology. Consultation or co-management with a retina specialist is recommended. [Level 5]
Patients with advanced ARMD should be considered for early referral for low-vision services. Vision impairment in patients with wet ARMD can prevent them from performing activities of daily living, and several aids are available to allow patients to read and perform other tasks